Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

BACKGROUND: This multicentre, randomised, double-blinded, placebo-controlled, phase II/III trial aimed to evaluate an oral THC:CBD (tetrahydrocannabinol:cannabidiol) cannabis extract for prevention of refractory chemotherapy-induced nausea and vomiting (CINV). Here we report the phase II component results. PATIENTS AND METHODS: Eligible patients experienced CINV during moderate-to-high emetogenic intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Study treatment consisted of one cycle of 1-4 self-titrated capsules of oral THC 2.5 mg/CBD 2.5 mg (TN-TC11M) three times daily, from days -1 to 5, and 1 cycle of matching placebo in a crossover design, then blinded patient preference for a third cycle. The primary end point was the proportion of participants with complete response during 0-120 h from chemotherapy. A total of 80 participants provided 80% power to detect a 20% absolute improvement with a two-sided P value of 0.1. RESULTS: A total of 81 participants were randomised; 72 completing two cycles were included in the efficacy analyses and 78 not withdrawing consent were included in safety analyses. Median age was 55 years (range 29-80 years); 78% were female. Complete response was improved with THC:CBD from 14% to 25% (relative risk 1.77, 90% confidence interval 1.12-2.79, P = 0.041), with similar effects on absence of emesis, use of rescue medications, absence of significant nausea, and summary scores for the Functional Living Index-Emesis (FLIE). Thirty-one percent experienced moderate or severe cannabinoid-related adverse events such as sedation, dizziness, or disorientation, but 83% of participants preferred cannabis to placebo. No serious adverse events were attributed to THC:CBD. CONCLUSION: The addition of oral THC:CBD to standard antiemetics was associated with less nausea and vomiting but additional side-effects. Most participants preferred THC:CBD to placebo. Based on these promising results, we plan to recruit an additional 170 participants to complete accrual for the definitive, phase III, parallel group analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001036404; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370473&isReview=true.

Effects of dried plum supplementation on bone metabolism in adult C57BL/6 male mice.

Dietary supplementation of dried plum (DP) prevents bone loss and restores bone mass in osteopenic animal models. This study was designed to determine the effects of DP supplementation on bone metabolic activity over time using adult (6-month-old) male C57BL/6 mice (n = 40) receiving control (CON = AIN93 M) or CON+DP 25 % (w/w) diets for 4 or 12 weeks. After 4 weeks of treatment, animals consuming the DP diet had a higher whole-body bone mineral density, vertebral trabecular bone volume (BV/TV), and femoral cortical thickness compared to the CON animals. In the distal metaphysis of the femur, BV/TV was increased in the DP-treated animals, but only after 12 weeks. Bone histomorphometric analyses revealed that DP decreased osteoblast surface (67 %) and osteoclast surface (62 %) at 4 weeks, but these surfaces normalized to the CON animals by 12 weeks. Coincident with these changes, the mineralizing surface (MS/BS) and cancellous bone formation rate (BFR/BS) were reduced at 4 weeks in the DP group compared to the CON, but by 12 weeks of DP supplementation, BFR/BS (~twofold) and MS/BS (~1.7-fold) tended to be increased (p < 0.10). The relative abundance of RNA for key regulators of osteoblast and osteoclast differentiation and indicators of osteoblast activity were reduced in the DP group at 4 weeks with no difference between groups at 12 weeks. These results indicate that supplementing the diet with DP initially suppressed cancellous bone turnover, but a biphasic response occurs over time, resulting in a positive effect on bone mass and structure.

Overexpression of protein S100A4 is independently associated with overall survival in stage C colonic cancer but only in cytoplasm at the advancing tumour front.

PURPOSE: S100A4, a multifunctional protein, has been linked to the invasive growth and metastases of several human cancers. This study investigated the association between S100A4 and overall survival and other clinicopathological features in patients with stage C colonic cancer. METHODS: Clinical and pathological data were obtained from a prospective hospital registry of 409 patients who had a resection for stage C colonic cancer. Tissue microarrays for immunohistochemistry were constructed from archived tissue. S100A4 staining intensity and percentage of stained cells were assessed in nuclei and cytoplasm for both the central part of the tumour and at the advancing front. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: Only a high percentage of cells with S100A4 cytoplasmic staining in frontal tissue was associated with poor survival (hazard ratio, 1.6; 95 % CI 1.1-2.2; p = 0.008) after adjustment for other prognostic variables. There was no association between frontal cytoplasmic S100A4 expression and any of 13 other clinicopathological variables. CONCLUSIONS: High expression of S100A4 in cytoplasm at the advancing front of stage C colonic tumours indicates a poor prognosis. Whether S100A4 can predict response to adjuvant chemotherapy remains to be investigated in a randomised clinical trial.

Health-related quality of life and financial impact of caring for a child with Thalassaemia Major in the UK.

BACKGROUND: Thalassaemia Major (TM) is a serious condition characterized by life-long dependence on blood transfusions and chelation therapy. Our aim was to determine health-related quality of life (HRQOL) in children with TM living in the UK, and the impact of caring for a child receiving National Health Service treatment on family finances. METHODS: This was a cross-sectional assessment of HRQOL in children (n= 22) with TM aged 8-18 years. Children were recruited from three UK Paediatric Haematology and Bone Marrow Transplant centres. Mothers completed measures of their child's HRQOL [PedsQL 4.0 (Measurement Model for the Pediatric Quality of Life Inventory, James W. Varni PhD, PedMetrics, Quantifying the Qualitative SM, Copyright 1998-2009)] and behaviour (Strengths and Difficulties questionnaire), and the impact of caring for the child on family finances. RESULTS: Child behaviour was within the normal range but child HRQOL was significantly lower than population norms. Family financial concerns associated with TM were associated with poorer child HRQOL (P= 0.020). CONCLUSIONS: Thalassaemia Major poses a considerable challenge to child HRQOL, well documented in areas of the world where TM is prevalent. Despite the availability of National Health Service care and financial benefits our study suggests a similar burden in the UK.

Predictive markers for haematological toxicity of pemetrexed.

Pemetrexed is a multi-targeted anti metabolite that inhibits several key folate-dependent enzymes in the thymidine and purine biosynthetic pathways, including thymidylate synthase. It is currently approved for use in patients with non-small cell lung cancer and malignant mesothelioma. The sporadic and unpredictable occurrence of haematological toxicities of pemetrexed leading to potentially life threatening complications during the early developmental phase, prompted urgent need to identify potential predictive factors for haematological toxicities from pemetrexed. There is a well established association between elevated plasma homocysteine concentration, which is indicative of impaired functional folate status, and increased risk of haematological toxicity from pemetrexed. The decrease in incidence of toxicity after vitamin supplementation confirms the importance of functional folate status as a predictor for haematological toxicity. We review other factors that have a documented impact on haematological toxicity, including pemetrexed schedule, and pharmacokinetic parameters that are indicative of the extent of drug exposure. Further potential factors are explored in this review, such as the genotype of the pemetrexed metabolising enzymes and varying incidences of polymorphism of these genotypes in different ethnic groups that may account for the ethnic differences in neutropenic response to pemetrexed.

Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial.

BACKGROUND: Substantial numbers of cancer patients use complementary medicine therapies, even without a supportive evidence base. This study aimed to evaluate in a randomized controlled trial, the use of Medical Qigong (MQ) compared with usual care to improve the quality of life (QOL) of cancer patients. PATIENTS AND METHODS: One hundred and sixty-two patients with a range of cancers were recruited. QOL and fatigue were measured by Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Fatigue, respectively, and mood status by Profile of Mood State. The inflammatory marker serum C-reactive protein (CRP) was monitored serially. RESULTS: Regression analysis indicated that the MQ group significantly improved overall QOL (t(144) = -5.761, P < 0.001), fatigue (t(153) = -5.621, P < 0.001), mood disturbance (t(122) =2.346, P = 0.021) and inflammation (CRP) (t(99) = 2.042, P < 0.044) compared with usual care after controlling for baseline variables. CONCLUSIONS: This study indicates that MQ can improve cancer patients' overall QOL and mood status and reduce specific side-effects of treatment. It may also produce physical benefits in the long term through reduced inflammation.

Methyl palmitate, an acaricidal compound occurring in green walnut husks.

Walnut, Juglans regia L., is known for its insecticidal activities to a range of herbivores and microbes. Isolation and identification of bioactive compounds from walnut is a potential approach for the development of new pesticides. Laboratory experiments were carried out to investigate the acaricidal activities of green husk extracts of walnut. Bioassay-guided fractionation of petroleum-ether extracts of walnut led to the identification of a common plant-borne fatty acid ester, methyl palmitate (MP), which produced strong acaricidal activity (62.8% mortality) at 1 mg/ml at 24 h. The structure of MP was characterized with infrared spectrum and NMR, and the identification of MP confirmed using an authentic standard on high-performance liquid chromatography. Based on a slide dip bioassay, 10 mg/ml MP provided 97.9% mortality against adults of Tetranychus cinnabarinus (Boisduval) (Acari: Tetranychidae), whereas mortality against eggs was much lower (57.2%).

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules.

The purpose of this study was to investigate the utility of plasma pharmacokinetic and pharmacodynamic measures including plasma deoxynucleosides, homocysteine and methylmalonic acid concentrations in understanding the time course and extent of the inhibition of thymidylate synthase (TS) by pemetrexed in the context of a phase I/II combination study with vinorelbine. Eighteen patients received supplementation with folic acid and Vitamin B(12) 1 week before beginning treatment with pemetrexed and vinorelbine administered in a dose-escalating manner on a 21-day cycle. Heparinised blood samples were collected from consenting patients in the first cycle for pharmacokinetic analyses and in the first two cycles for determination of plasma thymidine, deoxyuridine, homocysteine and methylmalonic acid concentrations. These values were correlated with response and toxicity. Plasma deoxyuridine was used as a measure of TS inhibition, and concentrations of deoxyuridine were significantly elevated relative to baseline on days 1 (P<0.01), 2 (P<0.001) and 3 (P<0.05) after treatment at all pemetrexed dose levels (400-700 mg m(-2)). The magnitude of deoxyuridine elevation correlated with pemetrexed area under the plasma concentration-time curve (AUC) (r(2)=0.23, P<0.05). However, deoxyuridine concentrations returned to baseline between 8 and 15 days after treatment with pemetrexed, suggesting that inhibition of TS was not durable. Pemetrexed AUC correlated with the percentage decline (relative to baseline) in both platelets (r(2)=0.58, P<0.001) and leucocytes (r(2)=0.26, P<0.05) at day 8. Baseline homocysteine was also significantly correlated with these measures of haematological toxicity (r(2)=0.37, P<0.01 and r(2)=0.39, P<0.01, respectively). In addition, there was a significant reduction of plasma homocysteine on days 8 (P<0.005) and 15 (P<0.05) in cycle 1 compared to baseline values. The results suggest that the TS inhibitory effects of pemetrexed are short-lived and make the case for a more frequent schedule of administration such as every 2 weeks. The lack of protracted TS inhibition may be due to concomitant vitamin administration, and this may be the mechanism by which vitamins prevent life-threatening toxicity from pemetrexed. Baseline homocysteine concentration remains a predictive marker for haematological toxicity even following folate supplementation.

Acaricidal activity of Juglans regia leaf extracts on Tetranychus viennensis and Tetranychus cinnabarinus (Acari: Tetranychidae).

Leaf extracts of the walnut, Juglans regia L., were evaluated under laboratory conditions to determine their acaricidal activity on the mites Tetranychus cinnabarinus (Boisduval) and Tetranychus viennensis Zacher (Acari: Tetranychidae). Extracts had both contact and systemic toxicity to these mites. The four solvents tested for preparing crude extracts were petroleum ether, chloroform, ethyl acetate, and methanol. Methanol was the most efficient solvent, with an extraction rate from 17.06 + 0.80 to 20.27 +/- 0.28%. Petroleum ether was the least effective solvent, with extraction rates from 2.30 +/- 0.13 to 2.71 +/- 0.13%. However, the crude extracts with petroleum ether resulted in the highest mite mortality (79.04 +/- 0.52%) in a slide dip bioassay. Mites mortalities from the concentrated extracts prepared by chloroform, ethyl acetate, methanol, or distilled water were significantly lower than petroleum ether. The mean lethal concentrations (LC50) of the extracts from petroleum ether, chloroform, ethyl acetate, methanol, and distilled water to the two mite species were 0.73 +/- 0.04, 1.66 +/- 0.28, 4.96 +/- 0.35, 7.45 +/- 0.67, and 9.91 +/- 0.32 mg/ml, respectively. After liquid chromatography and thin-layer chromatography, the concentrated extracts of petroleum ether were separated into eight fractions and tested for acaricidal activity. Fraction 6 produced significantly higher mite mortality rates than the other groups, killing approximately 90% of both species.

Randomized comparison of a nutrient-dense formula with an energy-supplemented formula for infants with faltering growth.

INTRODUCTION: The practice of supplementing standard infant formula with energy for infants with faltering growth has been widespread. This increases energy density but disturbs the protein : energy ratio, and increases risks of microbial contamination and errors in feed preparation. This study aimed to compare the effectiveness of a nutrient-dense formula (NDF) with an energy-supplemented formula (ESF) in infants with faltering growth. METHODS: In an open, parallel, randomized study, 49 infants with faltering growth were randomized to receive a NDF (4.2 kJ mL(-1)) or an ESF (4.2 kJ mL(-1)), for 6 weeks. Anthropometry, biochemistry, feed intake, stool and vomit frequency were collected. RESULTS: No significant differences in tolerance, feed volumes or energy intakes were recorded but the NDF group received 42% more protein and 15-40% more vitamins and minerals. Blood urea concentration in the ESF group fell by 50% over the trial period, suggesting a suboptimal protein : energy ratio in the ESF feed. The NDF group retained a normal mean blood urea concentration, a higher urinary potassium concentration and did not have the significant fall in length z-score seen in the ESF group. CONCLUSION: Increasing the energy content of normal infant formula without also increasing protein and micronutrients should not be practiced in infants with faltering growth.

Irofulven as first line therapy in recurrent or metastatic gastric cancer: a phase II multicenter study by the Cancer Therapeutics Research Group (CTRG).

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of irofulven, a DNA interacting acylfulvene analog, as first line therapy for patients with recurrent or metastatic gastric cancer. PATIENTS AND METHODS: Twenty-three patients with recurrent or metastatic gastric cancer received irofulven at a dose of 0.45 mg/kg administered intravenously over 30-min infusion (up to a maximum of 50 mg), on days 1 and 8, every 3 weeks. RESULTS: The median number of cycles delivered per patient was 2 (range 1-6). Two patients (9%) had >or= 1-week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, dose reductions were required in seven patients (30%); dose omitting occurred in five patients (22%). Grade 3/4 anemia and neutropenia occurred in 22 and 17% of patients, respectively. There was no grade 4 thrombocytopenia and no neutropenic fever was observed. Of the 20 evaluable patients, there were no responses observed, 3 patients had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55-9.39). CONCLUSIONS: Irofulven was tolerated at the dose of 0.45 mg/kg on days 1 and 8, every 3 weeks but showed no evidence of antitumor activity in patients with advanced gastric cancer.

Auditory motion affects visual biological motion processing.

The processing of biological motion is a critical, everyday task performed with remarkable efficiency by human sensory systems. Interest in this ability has focused to a large extent on biological motion processing in the visual modality (see, for example, Cutting, J. E., Moore, C., & Morrison, R. (1988). Masking the motions of human gait. Perception and Psychophysics, 44(4), 339-347). In naturalistic settings, however, it is often the case that biological motion is defined by input to more than one sensory modality. For this reason, here in a series of experiments we investigate behavioural correlates of multisensory, in particular audiovisual, integration in the processing of biological motion cues. More specifically, using a new psychophysical paradigm we investigate the effect of suprathreshold auditory motion on perceptions of visually defined biological motion. Unlike data from previous studies investigating audiovisual integration in linear motion processing [Meyer, G. F. & Wuerger, S. M. (2001). Cross-modal integration of auditory and visual motion signals. Neuroreport, 12(11), 2557-2560; Wuerger, S. M., Hofbauer, M., & Meyer, G. F. (2003). The integration of auditory and motion signals at threshold. Perception and Psychophysics, 65(8), 1188-1196; Alais, D. & Burr, D. (2004). No direction-specific bimodal facilitation for audiovisual motion detection. Cognitive Brain Research, 19, 185-194], we report the existence of direction-selective effects: relative to control (stationary) auditory conditions, auditory motion in the same direction as the visually defined biological motion target increased its detectability, whereas auditory motion in the opposite direction had the inverse effect. Our data suggest these effects do not arise through general shifts in visuo-spatial attention, but instead are a consequence of motion-sensitive, direction-tuned integration mechanisms that are, if not unique to biological visual motion, at least not common to all types of visual motion. Based on these data and evidence from neurophysiological and neuroimaging studies we discuss the neural mechanisms likely to underlie this effect.

Acaricidal activities of extracts of Kochia scoparia against Tetranychus urticae, Tetranychus cinnabarinus, and Tetranychus viennensis (Acari: Tetranychidae).

Extracts of an annual herbaceous plant, Kochia scoparia (L.) Schrad (Macrophomina), were bioassayed to determine their acaricidal activities against Tetranychus urticae Koch, Tetranychus cinnabarinus (Boisduval), and Tetranychus viennensis Zacher (Acari: Tetranychidae) in the laboratory. Extracts had both contact and systemic toxicity to these mites. Three solvents were tested for preparing crude extracts: petroleum ether, chloroform, and methanol. Methanol was the most effective solvent, extracting 3.11-4.53% of the acaricide. Petroleum ether was the least effective solvent, extracting 1.25-1.54%. However, extracts with chloroform resulted in the highest mite mortality (78.86%), and ultrasound-assisted extraction required the least time (10 min). Concentrated extracts were prepared using chloroform, methyl acetate, or distilled water as a solvent. Mite mortalities from the concentrated extracts by methyl acetate or distilled water were significantly lower than those by chloroform. The mean lethal concentrations (LC50) of the extracts by chloroform, methyl acetate, and distilled water to the mites were 0.71 +/- 0.06, 2.08 +/- 0.16 and 8.75 +/- 0.062 mg/ml, respectively. After liquid chromatography and thin layer chromatography, the concentrated extracts by chloroform were separated into seven groups of isolated fractions and tested for acaricidal activity.

Increasing resistance to ciprofloxacin among isolates of Neisseria gonorrhoea in Dublin.

Neisseria gonorrhoeae cases are increasing in Ireland. Ciprofloxacin is often used as first line treatment for this infection in STI clinics. A retrospective study to analyze resistance in two Dublin clinics was undertaken. Cases were defined as patients from whom an isolate of N. gonorrhoea was recovered. All cases from two clinics between January 1997 and June 2003 were included. Antimicrobial resistance data was correlated with sex and sexuality. One thousand one hundred and eighty laboratory-confirmed cases were identified. Eighty seven percent were male. Sixty nine percent were MSM. Twenty seven percent of isolates demonstrated reduced susceptibility to penicillin and 6% to ciprofloxacin. Isolates with reduced susceptibility to ciprofloxacin increased year on year from 3.8% in 1997 to 15% in 2003. Prevalence of isolates of N. gonorrhoea with reduced susceptibility to ciprofloxacin has exceeded 10% in these clinics since 2002. In concordance with international guidelines, ceftriaxone became the treatment of choice for gonorrhoea in July 2003.

Effects of iron supplementation on binding activity of iron regulatory proteins and the subsequent effect on growth performance and indices of hematological and mineral status of young pigs.

Two experiments were conducted to evaluate the effects of supplemental Fe on the binding activity of iron regulatory proteins (IRP) and the subsequent effect on growth performance and indices of hematological and mineral status of young pigs. In Exp. 1, male pigs (n = 10; 1.8 kg; age = 14 +/- 1 h) were allotted by BW to two treatments (five pigs per treatment). Treatments administered by i.m. injection were as follows: 1) 1 mL of sterile saline solution (Sal); and 2) 1 mL of 200 mg Fe as Fe-dextran (Fe). Pigs were bled (d 0 and 13) to determine hemoglobin (Hb), hematocrit (Hct), transferrin (Tf), and plasma Fe (PFe), and then killed (d 13) to determine spontaneous and 2-mercaptoethanol (2-ME)-inducible IRP RNA binding activity in liver and liver and whole-body mineral concentrations. Contemporary pigs (n = 5; 2.2 kg; age = 14 +/- 2 h) were killed at d 0 to establish baseline (BL1) measurements. In Exp. 2, pigs (six pigs per treatment; 6.5 kg; age = 19 +/- 3 d) were fed a basal diet (Phase 1 = d 0 to 7; Phase 2 = d 7 to 21; Phase 3 = d 21 to 35) supplemented with 0 or 150 mg/kg of Fe as ferrous sulfate and killed at d 35 (18.3 kg; age = 54 +/- 3 d). In addition, pigs (n = 5; 5.9 kg; age = 19 +/- 3 d) were killed at the start of Exp. 2 to establish baseline (BL2) measurements, and liver samples were collected and analyzed for IRP RNA binding activity. In Exp. 1, no difference (P = 0.482) was observed in ADG. On d 13, Fe-treated pigs had greater (P = 0.001) Hb, Hct, and PFe and less (P = 0.002) Tf than Sal-treated pigs. Whole-body Fe concentration was greater (P = 0.002) in Fe- vs. Sal-treated pigs. Treated pigs (Fe or Sal) had greater (P = 0.006) whole-body Cu and less (P = 0.002) whole-body Ca, Mg, Mn, P, and Zn concentrations than BL1. Liver Fe concentration was greater (P = 0.001) in Fe- vs. Sal-treated pigs, but liver Fe concentration of Sal-treated pigs was less (P = 0.001) than that of BL1 pigs. Sal-treated pigs had greater (P = 0.004) spontaneous IRP binding activity than Fe-treated pigs. In Exp. 2, spontaneous and 2-ME inducible IRP binding activities were greater (P = 0.013 and 0.005, respectively) in pigs fed diets containing 0 vs. 150 mg of added Fe/kg of diet. Moreover, pigs fed either treatment for 35 d had greater (P = 0.001) 2-ME inducible IRP binding activity than BL2 pigs. Results indicate that IRP binding activity is influenced by Fe supplementation. Subsequently, other indicators of Fe status are affected via the role of IRP in posttranscriptional expression of Fe storage and transport proteins.

Australian experience of a modified schedule of FOLFOX with high activity and tolerability and improved convenience in untreated metastatic colorectal cancer patients.

This study determined the efficacy and safety of a modified FOLFOX regimen that improved patient convenience without compromising oxaliplatin dose intensity. A total of 62 patients with previously untreated metastatic colorectal cancer were enrolled to receive, entirely as outpatients, 2-weekly cycles of oxaliplatin 100 mg m(-2) i.v. over 2 h, together with leucovorin 400 mg m(-2) over 2 h, 5-fluorouracil (5-FU) 400 mg m(-2), bolus, followed by a 46-h infusion of 5-FU at 2.4 g m(-2). Treatment was given until progression or unmanageable toxicity. In all, 61 patients received > or =one oxaliplatin dose and a median of 11 treatment cycles (range 1-20 cycles); 22 (36%) reported grade 3/4 neutropenia and 13 patients (21%) experienced grade 3 neurotoxicity; 16 patients (26%) discontinued treatment due to disease progression or death, 15 (25%) due to neurotoxicity and six (10%) due to haematological toxicity. Of the 56 eligible patients, complete or partial responses were observed in 29 or 52% (95% confidence interval 38-65%). Median progression-free survival was 8.2 months (7.1-9.9) and median overall survival was 18.7 months (14.0-23.4). In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity.

DTI mapping of human brain connectivity: statistical fibre tracking and virtual dissection.

Several approaches have been used to trace axonal trajectories from diffusion MRI data. If such techniques were first developed in a deterministic framework reducing the diffusion information to one single main direction, more recent approaches emerged that were statistical in nature and that took into account the whole diffusion information. Based on diffusion tensor MRI data coming from normal brains, this paper presents how brain connectivity could be modelled globally by means of a random walk algorithm. The mass of connections thus generated was then virtually dissected to uncover different tracts. Corticospinal, corticobulbar, and corticothalamic tracts, the corpus callosum, the limbic system, several cortical association bundles, the cerebellar peduncles, and the medial lemniscus were all investigated. The results were then displayed in the form of an in vivo brain connectivity atlas. The connectivity pattern and the individual fibre tracts were then compared to known anatomical data; a good matching was found.

Patterns of calcium-binding proteins in human inferior colliculus: identification of subdivisions and evidence for putative parallel systems.

The subdivisions of human inferior colliculus are currently based on Golgi and Nissl-stained preparations. We have investigated the distribution of calcium-binding protein immunoreactivity in the human inferior colliculus and found complementary or mutually exclusive localisations of parvalbumin versus calbindin D-28k and calretinin staining. The central nucleus of the inferior colliculus but not the surrounding regions contained parvalbumin-positive neuronal somata and fibres. Calbindin-positive neurons and fibres were concentrated in the dorsal aspect of the central nucleus and in structures surrounding it: the dorsal cortex, the lateral lemniscus, the ventrolateral nucleus, and the intercollicular region. In the dorsal cortex, labelling of calbindin and calretinin revealed four distinct layers.Thus, calcium-binding protein reactivity reveals in the human inferior colliculus distinct neuronal populations that are anatomically segregated. The different calcium-binding protein-defined subdivisions may belong to parallel auditory pathways that were previously demonstrated in non-human primates, and they may constitute a first indication of parallel processing in human subcortical auditory structures.

Utility of metabolic stability screening: comparison of in vitro and in vivo clearance.

1. The ability of hepatic microsomal metabolic stability assessments to predict in vivo clearance in rat has been retrospectively evaluated for 1,163 compounds from 48 programmes of chemistry. Using a simple binary classification system, the in vivo clearances of approximately 64% of the compounds were correctly classified. 2. About 24% of compounds were metalbolically stable yet had clearance greater than half of liver blood flow in vivo. This might be expected as microsomes only contain a limited number of fully functioning drug-metabolizing enzymes and cannot be expected to account for extrahepatic or non-metabolic clearance processes. 3. About 13% of compounds had in vivo clearances of less than half liver blood flow despite being classified as metabolically unstable. Despite overcoming metabolic instability, these compounds had other undesirable properties and were generally more highly bound to plasma proteins, had smaller volumes of distribution (and shorter half-lives despite their clearance) and were more inhibitory against the major human cytochrome P450s. 4. Taking plasma protein binding into consideration reduced the proportion of misclassified low-clearance compounds but did not improve the overall success appreciably. Somewhat surprisingly, human microsomes were nearly as effective as rat microsomes at classifying rat in vivo clearance.